Existing products containing buprenorphine hydrochloride are TEMGESIC (trade mark), SUBUTEX (trademark) and SUBOXONE (trade mark); products sold for the treatment of moderate to severe pain or for the treatment of opiate addiction. TEMGESIC and SUBUTEX contain buprenorphine hydrochloride as the sole active ingredient; SUBOXONE contains buprenorphine hydrochloride and naloxone, as co-active ingredients.
It has been stated in WO 2005/117838 that buprenorphine hydrochloride shows degradation in acid or alkaline conditions and may be degraded by oxidation.
One attempt to stabilise buprenorphine is provided in U.S. Pat. No. 6,365,596, which discloses pharmaceutical compositions containing buprenorphine and at least one antioxidant in a molar ratio, antioxidant to buprenorphine, in the range 1:1 to 3:1. It is also mentioned in U.S. Pat. No. 6,365,596 that stability is improved by avoiding the presence of magnesium ions, and polyvinylpyrrolidone.
In the invention of WO 2005/117838 the improvement is to stabilise buprenorphine by using a lower concentration of an antioxidant, compared with U.S. Pat. No. 6,365,596 (preferably 1:1000-1:10, molar ratio, antioxidant: buprenorphine), and a chelating agent (preferably 0.01-5%, wt:wt).
We see an inherent undesirability in having to use a large amount of an antioxidant (per U.S. Pat. No. 6,365,596), or an antioxidant and a chelating agent together (per WO 2005/117838), in order to stabilise buprenorphine and/or salts or esters thereof.